Title: Effectiveness of Zonisamide in the Treatment of Alcohol-Dependent Veterans ABSTRACT: Veterans have a high prevalence of alcohol dependence (AD), and those with AD also have a high rate of co-occurring psychiatric illnesses. Zonisamide is an extremely promising medicine for treating AD and managing other clinical problems including psychiatric disorders. Zonisamide is an affordable, generic anticonvulsant with unique actions on the major neurotransmitter systems involved in alcoholism, and it has neuroprotective effects. We recently completed a randomized, placebo- controlled pilot study of zonisamide in treating AD that showed significant reductions in heavy drinking, overall drinking, and alcohol craving. Zonisamide was very well tolerated in this study. In this application, we propose a larger (N = 160), 14-week, randomized, double-blind, placebo-controlled, effectiveness study of zonisamide in reducing heavy drinking and improving outcomes in a representative population of heavy-drinking veterans with AD. We describe zonisamide's potential to break through the barriers in the treatment of veterans with AD as well as its unique pharmacology that brings innovation to alcoholism treatment. An inexpensive, hypothesis-driven, exploratory, translational, pharmacogenetic component adds to the innovation and will work towards optimizing outcomes and personalizing treatment for veterans.